SUMMARY/ABSTRACT Traumatic Brain Injury (TBI) is a major health problem in the US. It is estimated that over 3 million people live with disabilities caused by TBI with many suffering from disorders including depression or anxiety. The goal of this research proposal is to elucidate how TBI affects the function of peripheral systems and alters the microbiome and the resultant impact on TBI-induced affective disorders. Our preliminary data indicate that CCI causes a rapid shift in microbiota diversity within 24h of TBI, including a dramatic change in the diversity of the psychoactive Lactobacillus family. Based on our data, we are testing the hypothesis that changes to commensal gut microbiota after TBI modulates brain inflammation and drives the development of affective disorder phenotypes in mice. Using 16S rRNA gene sequencing analysis, we will look for differentially abundant taxa, comparing sham to TBI mice. We will also examine if these changes are altered by injury severity, and we will study the impact of sex on the outcome. To test our hypothesis, we will: 1) identify differentially abundant bacteria before and after mild and severe control cortical impact by 16S and metagenomics analysis; 2) perform rescue experiments with probiotics containing TBI-impacted bacteria to study the progression of neuroinflammation process, neuronal death, and neurobehavioral abnormalities; and 3) compare the recovery of germ-free mice exposed to TBI following either sham or TBI mouse fecal transplants. This project will help to further elucidate the gut-brain axis cross-talk and clarify the role of the microbiome on recovery from TBI. Specifically, this project will explore if fecal transplants alter brain function and represent a potential novel therapeutic avenue for TBI. In summary, this research is based on the scientific premise that bacterial within the gut and bacterial diversity can impact behavior, and that brain injury can disrupt diversity in a healthy gut microbiome. !